Radiotherapy plays a critical role in the definitive management of early stage and locally advanced non- small cell lung cancer (NSCLC), the number one cause of cancer deaths in the United States. Two important challenges in the management of NSCLC patients treated with radiotherapy are the inability to detect microscopic residual disease and the difficulty of distinguishing between recurrent malignancy and post-radiation normal tissue changes on follow-up radiographic studies. These shortcomings prevent design and testing of individualized treatment strategies that could potentially increase cure rates and suggest that improved methods for following patients after treatment are needed. Our goal is to test a novel approach for detecting the presence of residual or recurrent disease in NSCLC patients treated with radiotherapy. Somatic alterations in the genomes of cancer cells represent ideal biomarkers, since they can define patient- and tumor-specific signatures that distinguish cancer cells from non-malignant counterparts. Cancers continually release genomic DNA into the circulation, potentially allowing noninvasive access to cancer genomes and quantitation of disease burden. We have designed and implemented a novel, high throughput sequencing-based technique for measurement of circulating tumor-derived DNA termed CAPP- Seq (CAncer Personalized Profiling in by deep Sequencing). We propose to evaluate the utility of ctDNA analysis via CAPP-Seq in NSCLC patients treated with radiotherapy and to explore mechanisms of ctDNA release and clearance in human patients. Taken together, these studies will lay the groundwork for prospective clinical trials that will test personalization of radiotherpy-based therapeutic strategies using ctDNA analysis.